HIV-1 Promotes Renal Tubular Epithelial Cell Protein Synthesis: Role of mTOR Pathway

Abstract

Tubular cell HIV-infection has been reported to manifest in the form of cellular hypertrophy and apoptosis. In the present study, we evaluated the role of mammalian target of rapamycin (mTOR) pathway in the HIV induction of tubular cell protein synthesis. Mouse proximal tubular epithelial cells (MPTECs) were transduced with either gag/pol-deleted NL4-3 (HIV/MPTEC) or empty vector (Vector/MPTEC). HIV/MPTEC showed enhanced DNA synthesis when compared with Vector/MPTECs by BRDU labeling studies. HIV/MPTECs also showed enhanced production of β-laminin and fibronection in addition to increased protein content per cell. In in vivo studies, renal cortical sections from HIV transgenic mice and HIVAN patients showed enhanced tubular cell phosphorylation of mTOR. Analysis of mTOR revealed increased expression of phospho (p)-mTOR in HIV/MPTECs when compared to vector/MPTECs. Further downstream analysis of mTOR pathway revealed enhanced phosphorylation of p70S6 kinase and associated diminished phosphorylation of eEF2 (eukaryotic translation elongation factor 2) in HIV/MPTECs; moreover, HIV/MPTECs displayed enhanced phosphorylation of eIF4B (eukaryotic translation initiation factor 4B) and 4EBP-1 (eukaryotic 4E binding protein). To confirm our hypothesis, we evaluated the effect of rapamycin on HIV-induced tubular cell downstream signaling. Rapamycin not only attenuated phosphorylation of p70S6 kinase and associated down stream signaling in HIV/MPTECs but also inhibited HIV-1 induced tubular cell protein synthesis. These findings suggest that mTOR pathway is activated in HIV-induced enhanced tubular cell protein synthesis and contributes to tubular cell hypertrophy.

Renin angiotensin system modulates mTOR pathway through AT2R in HIVAN

“…We have previously reported that HIV not only phosphorylated mTOR but also activated mTOR pathway in tubular cells (Rehman et al, 2012). Additionally, we reported that HIV stimulated tubular cell renin production through down regulation of VDR (Chandel et al, 2013; Salhan et al, 2012b).…”

“…Modalities which either blocked the production of Ang II or inhibited the effect of Ang II have been reported to slow down the progression of HIVAN (Bird et al, 1989; Burns et al, 1999; Kimmel et al, 2003); moreover, infusion of Ang II accelerated the progression of renal lesions in a mouse model of HIVAN (Ideura et al, 2007). Recently, mTOR pathway has been demonstrated to play an important role in the development of proliferative HIVAN phenotype in HIVAN (Kumar et al, 2010; Rai et al, 2013; Rehman et al, 2012). We hypothesized that renin angiotensin system may be contributing to the activation of mTOR pathway in HIVAN.…”

mTOR plays a critical role in p53-induced oxidative kidney cell injury in HIVAN

“…Interestingly, the mTOR pathway has been reported to contribute to the pathogenesis of diabetic and HIV-associated nephropathy (25,26). Moreover, the effector molecules of these entities-glucose and HIVhave also been reported to activate both kidney cell mTOR and p53 pathways (23,35,36,46). However, there are no data on cross talk between mTOR and p53 in the development of these diseases.…”

“…We have previously demonstrated (25,35) that kidney cells displayed enhanced expression of phosphomTOR in both HIVAN mice and HIVAN patients. In in vivo studies, inhibition of mTOR pathway slowed down the progression of HIVAN, whereas in in vitro studies inhibition of mTOR pathway prevented HIV-induced tubular cell growth.…”

Sirolimus modulates HIVAN phenotype through inhibition of epithelial mesenchymal transition

“…Since mTOR is an important cellular pathway for protein synthesis, it is required for cellular proliferation. As regards molecular events are concerned in HIV-induced activation of mTOR pathway, mTORC1 activation proceeds with the sirolimus-sensitive phosphorylation of 4EBP1 which by freeing eIF4E promots the initiation phase of mRNA translation in kidney cells (Rehman et al, 2012). Activation of mTORC1 leads to the phosphorylation of p70S6 kinase, which phosphorylates eIF4B on Ser 422 .…”